Rising rates of obesity and type II diabetes are a pervasive threat to health and healthcare in the United States. Numerous means to counter the trend are being explored. These include lifestyle changes, bariatric surgeries and pharmaceuticals. Among the latter, numerous drug candidates have failed to meet efficacy and/or safety criteria - often because of unanticipated side effects associated with targeting complex receptor systems in the brain. We propose studies to validate a new enzyme target in the stomach. This enzyme functions outside of the central nervous system. Ghrelin is a peptide hormone secreted by X/A cells in the gastric mucosa. In humans, systemic administration of ghrelin promotes feeding and blocks release of insulin from pancreatic ?-cells. Ghrelin matures from a 117-amino acid precursor, and gains its endocrine functions only when acylated on Ser-3 with octanoate. Data show this modification is performed by ghrelin O-acyl transferase (GOAT), a newly discovered member of the membrane bound O-acyl transferase (MBOAT) family of enzymes. To date, GOAT has no other known functions, and octanoylation appears to be a modification unique to the ghrelin/GOAT system. The selectivity of GOAT, its localization to the digestive tract rather than the central nervous system, and its essential role in ghrelin maturatio make the enzyme a prime candidate for drug discovery programs. A recent report describing a peptide inhibitor of GOAT with activity in vivo furthers this view. GO-CoA-Tat, a 'bi-substrate' mimetic, decreases circulating ghrelin levels in mice, reduces weight gain in mice fed a high fat diet, and improves glucose tolerance in wild type animals. The hypothesis that chronic inhibition of GOAT may improve insulin sensitivity in the setting of diet-induced or genetic obesity, however, has not been tested. In collaboration with Michael Brown and Joseph Goldstein at the University of Texas Southwestern Medical Center, we have discovered small peptidomimetics that strongly inhibit GOAT in vitro. These compounds are orders of magnitude more potent than other known inhibitors, and are markedly more drug-like than GO-CoATat. We propose to further refine these lead structures for use in vivo. Molecules that retain potency at the target and possess favorable pharmacokinetic profiles will be thoroughly evaluated in rodent disease models. Through these studies we will ascertain whether GOAT inhibitors represent a new strategy for treating metabolic disease in animal models. The experiments will lay a foundation for future translational studies aimed at targeting GOAT in human drug therapy.